Hyperthermia is a well known teratogen in animals and a suspected teratogen in humans. In addition to its teratogenic effects, acute hyperthermia also induces a heat shock response characterized by alterations in transcription and translation and the synthesis of heat shock proteins (hsps). Furthermore, a variety of teratogens are capable of inducing this heat shock, or more properly, stress response. Our long range goal, therefore, is to define the relationship between teratogen- induced stress response and the induction of birth defects. One of the specific aims of this proposal is to use high resolution two-dimensional gel electrophoresis coupled with computer-assisted image analysis to examine the hypothesis that the induction of a stress response in the mammalian embryo during the critical period of organogenesis can alter the established program of activation and inactivation of genetic loci essential for normal development. Mild hyperthermia can also induce a thermotolerant state that protects cells or embryos from the toxic effects of heat and other stress-inducing agents. Although the mechanisms underlying thermotolerance are not well understood, specific hsps (hsp 27 and 72) and antioxidant defenses (glutathione, superoxide dismutase and glutathione peroxidase) have been implicated. A second specific aim, therefore, is to use antibodies, cDNAs, enzyme assays, enzyme inhibitors and inducers to examine the hypothesis that specific hsps and/or antioxidant defenses play a role in the induction of thermotolerance in rodent embryos. Finally, we will construct transgenic mice in which specific hsps are constitutively expressed under the control of a beta-actin promoter to test the hypothesis that hsps play a direct role in the induction of thermotolerance in rodent embryos.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD022095-06A1
Application #
2198449
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1987-08-01
Project End
1997-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Mirkes, P E; Cornel, L M; Wilson, K L et al. (1999) Heat shock protein 70 (Hsp70) protects postimplantation murine embryos from the embryolethal effects of hyperthermia. Dev Dyn 214:159-70
Thayer, J M; Mirkes, P E (1997) Induction of Hsp72 and transient nuclear localization of Hsp73 and Hsp72 correlate with the acquisition and loss of thermotolerance in postimplantation rat embryos. Dev Dyn 208:227-43
Mirkes, P E; Cornel, L M; Park, H W et al. (1997) Induction of thermotolerance in early postimplantation rat embryos is associated with increased resistance to hyperthermia-induced apoptosis. Teratology 56:210-9
Bratton, S L; Jardine, D S; Mirkes, P E (1997) Constitutive synthesis of heat shock protein (72 kD) in human peripheral blood mononuclear cells: implications for use as a clinical test of recent thermal stress. Int J Hyperthermia 13:157-68
Mirkes, P E; Little, S A; Cornel, L et al. (1996) Induction of heat shock protein 27 in rat embryos exposed to hyperthermia. Mol Reprod Dev 45:276-84
Little, S A; Mirkes, P E (1995) Clusterin expression during programmed and teratogen-induced cell death in the postimplantation rat embryo. Teratology 52:41-54
Thayer, J M; Mirkes, P E (1995) Programmed cell death and N-acetoxy-2-acetylaminofluorene-induced apoptosis in the rat embryo. Teratology 51:418-29
Cunningham, M L; Mac Auley, A; Mirkes, P E (1994) From gastrulation to neurulation: transition in retinoic acid sensitivity identifies distinct stages of neural patterning in the rat. Dev Dyn 200:227-41
Fujinaga, M; Park, H W; Shepard, T H et al. (1994) Staurosporine does not prevent adrenergic-induced situs inversus, but causes a unique syndrome of defects in rat embryos grown in culture. Teratology 50:261-74
Mirkes, P E; Doggett, B; Cornel, L (1994) Induction of a heat shock response (HSP 72) in rat embryos exposed to selected chemical teratogens. Teratology 49:135-42

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